A priori and null in autism genetics: Lesson from 7,600 whole genome and 35,000 exome sequencing data

Joon-Yong An (joonan30@korea.ac.kr)

Department of Biosystem and Biomedical Science, Korea University

De novo mutations play an important role in human disorders that impair reproductive fitness, including autism spectrum disorder (ASD), severe developmental delay, epileptic encephalopathy, and a spectrum of congenital anomalies. Next generation sequencing technology has successfully estimated the contribution of de novo mutations to ASD and resulted in remarkable advances in our understanding of the genetic architecture of risk for ASD. Here I summarize the recent progress in ASD genetics and introduce two on-going projects from the Autism Sequencing Consortium (ASC), the largest research consortium for ASD genetics. First, I will discuss our latest study of whole exome sequencing, the largest exome sequencing study of ASD to date (n=35,584 total samples). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. We further assess functional and spatiotemporal convergence of risk genes in developing brains using bulk and single-cell gene expression. Then, we further examine noncoding variation in ASD using whole genome sequencing. Our latest work facilitates the first genome-wide evaluations of the contribution of de novo noncoding mutations from 7,608 samples in 1,902 ASD families, identifying 255,106 de novo mutations. In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, is significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, does demonstrate association with mutations localized to promoter regions. The strongest driver of this promoter signal emanates from evolutionarily conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD.


BLDG 110, Rm N104

Online with ZOOM: https://zoom.us/j/97475138941